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Organic arsenicals As efficient and highly specific linkers for protein/peptide–polymer conjugation
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Wilson, Paul, Anastasaki, Athina, Owen, Matthew R., Kempe, Kristian, Haddleton, David M., Mann, Sarah K., Johnston, Angus P. R., Quinn, John F., Whittaker, Michael R., Hogg, Philip J. and Davis, Thomas P. (2015) Organic arsenicals As efficient and highly specific linkers for protein/peptide–polymer conjugation. Journal of the American Chemical Society, 137 (12). pp. 4215-4222. doi:10.1021/jacs.5b01140 ISSN 0002-7863.
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Official URL: http://dx.doi.org/10.1021/jacs.5b01140
Abstract
The entropy-driven affinity of trivalent (in)organic arsenicals for closely spaced dithiols has been exploited to develop a novel route to peptide/protein–polymer conjugation. A trivalent arsenous acid (As(III)) derivative (1) obtained from p-arsanilic acid (As(V)) was shown to readily undergo conjugation to the therapeutic peptide salmon calcitonin (sCT) via bridging of the Cys1-Cys7 disulfide, which was verified by RP-HPLC and MALDI-ToF-MS. Conjugation was shown to proceed rapidly (t < 2 min) in situ and stoichiometrically through sequential reduction–conjugation protocols, therefore exhibiting conjugation efficiencies equivalent to those reported for the current leading disulfide-bond targeting strategies. Furthermore, using bovine serum albumin as a model protein, the trivalent organic arsenical 1 was found to demonstrate enhanced specificity for disulfide-bond bridging in the presence of free cysteine residues relative to established maleimide functional reagents. This specificity represents a shift toward potential orthogonality, by clearly distinguishing between the reactivity of mono- and disulfide-derived (vicinal or neighbors-through-space) dithiols. Finally, p-arsanilic acid was transformed into an initiator for aqueous single electron-transfer living radical polymerization, allowing the synthesis of hydrophilic arsenic-functional polymers which were shown to exhibit negligible cytotoxicity relative to a small molecule organic arsenical, and an unfunctionalized polymer control. Poly(poly[ethylene glycol] methyl ether acrylate) (PPEGA480, DPn = 10, Mn,NMR = 4900 g·mol–1, Đ = 1.07) possessing a pentavalent arsenic acid (As(V)) α-chain end was transformed into trivalent As(III) post-polymerization via initial reduction by biological reducing agent glutathione (GSH), followed by binding of GSH. Conjugation of the resulting As(III)-functional polymer to sCT was realized within 35 min as indicated by RP-HPLC and verified later by thermodynamically driven release of sCT, from the conjugate, in the presence of strong chelating reagent ethanedithiol.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry | ||||||
| Journal or Publication Title: | Journal of the American Chemical Society | ||||||
| Publisher: | American Chemical Society | ||||||
| ISSN: | 0002-7863 | ||||||
| Official Date: | 20 March 2015 | ||||||
| Dates: |
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| Volume: | 137 | ||||||
| Number: | 12 | ||||||
| Page Range: | pp. 4215-4222 | ||||||
| DOI: | 10.1021/jacs.5b01140 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access |
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